July 2011

Editors:
Michael Cibull, MD
Melissa Kesler, MD
Rouzan Karabakhtsian, MD
Megan Zhang, MD

• Endometrial and ovarian carcinomas with undifferentiated components
• Tumor thickness as an indicator of chemotherapy response in hepatic colorectal metastases
• Encapsulated papillary oncocytic neoplasms of the thyroid gland
• Fimbrial-ovarian carcinomas unified by altered p53, PTEN, and PAX2 expression
• Prognostic significance of p16^INK4a and HPV in oropharyngeal cancer
• Breast carcinoma with amplified HER2: a gene expression signature for trastuzumab resistance
• Initial margin status for invasive ductal carcinoma of the breast
• Evaluation of lymph node counts in primary retroperitoneal lymph node dissection

Endometrial and ovarian carcinomas with undifferentiated components

Carcinomas of the endometrium and ovary with undifferentiated components are uncommon neoplasms that have been shown to be clinically aggressive, and they are likely underdiagnosed. The authors identified 32 carcinomas with undifferentiated components—26 endometrial and six ovarian. Patients ranged in age from 21 to 76 years (median, 55 years); 40 percent of the patients were 50 years of age or younger. Most patients (representing 58 percent of endometrial and 83 percent of ovarian carcinomas with undifferentiated components) presented at advanced stages (FIGO grade III–IV). Pelvic and para-aortic lymph nodes were the most frequent sites of metastases. Twenty tumors, entirely undifferentiated, consisted of sheets of dyshesive, ovoid cells with uniform, large vesicular nuclei, whereas 12 tumors contained combinations of differentiated endometrioid adenocarcinoma with undifferentiated components. Although most undifferentiated tumors had a monotonous cytologic appearance without prominent stroma, six showed focal nuclear pleomorphism and eight cases had variably sized zones of rhabdoid cells in a background of myxoid stroma. The tumors were frequently misdiagnosed, and the diagnoses included FIGO grade II or III endometrioid carcinoma, carcinosarcoma, high-grade sarcoma including endometrial stromal sarcoma, neuroendocrine carcinoma, lymphoma, granulosa cell tumor, and epithelioid sarcoma. Up to 86 percent of the cases showed focal but strong keratin or epithelial membrane antigen staining, or both, with CK18 being the keratin stain that was most frequently positive. The tumors were predominantly negative for neuroendocrine markers, smooth muscle markers, and estrogen receptor/progesterone receptor. Mismatch repair protein expression by immunohistochemistry was evaluated in 17 cases, and eight (47 percent) were abnormal (seven with loss of MLH1/PMS2 and one with loss of MSH6). Followup was available for 27 patients, although it was very short in many cases, ranging from 0.5 to 89 months (median, nine months). Eleven patients (41 percent) died of the disease in 0.5 to 20 months; four were alive with disease; and 12 patients had no evidence of disease. The authors concluded that endometrial and ovarian carcinomas with undifferentiated components have a broad histologic differential diagnosis, but they show specific histologic features that should enable accurate diagnosis. These tumors can occur in young women, may be associated with microsatellite instability, and behave in a clinically aggressive manner.

Tafe LJ, Garg K, Chew I, et al. Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms. Mod Pathol. 2010:23:781–789.

Correspondence: Dr. R. A. Soslow at soslowr@mskcc.org
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Tumor thickness as an indicator of chemotherapy response in hepatic colorectal metastases

Pathologic indicators of therapy response lead to progress in treating hepatic colorectal metastases (HCRM). The authors observed that a majority of residual tumor cells are seen at the tumor-normal interface (TNI) in resected HCRM specimens and hypothesized that tumor thickness at this interface correlates with radiologic and pathologic response and recurrence-free survival (RFS). The authors conducted a study that included 103 patients with HCRM that was resected after preoperative chemotherapy with or without bevacizumab. Imaging response was assessed by response evaluation criteria in solid tumors (RECIST) and by recently described computed tomography morphology criteria. Pathologic response was categorized as complete (no tumor cells), major (fewer than 50 percent residual tumor cells), or minor (50 percent or more residual tumor cells). The maximum thickness of uninterrupted layers of tumor cells was measured perpendicular to the tumor-normal interface by two independent pathologists. This was followed by consensus review for discrepant cases. For specimens containing more than one tumor, the average tumor thickness at the tumor-normal interface was used. Sixty-five patients received oxaliplatin-based chemotherapy, 38 irinotecan-based chemotherapy, and 75 concurrent bevacizumab. A complete pathologic response was seen in nine patients, a major response in 44, and a minor response in 50. Median tumor thickness at the tumor-normal interface was 2.8 mm (interquartile range, 0.5 to 6 mm). Tumor thickness correlated better with radiologic response (P<0.0001) than with RECIST criteria (Spearman, r=0.35; P<0.001). Tumor thickness correlated with pathologic response (Spearman, r=80; P<0.0001). Greater thickness predicted shorter recurrence-free survival, and this correlation remained in multivariate analysis (P=0.015). Tumor thickness was smaller in patients treated with bevacizumab than in patients not given bevacizumab (P=0.03). The authors concluded that tumor thickness measured at the tumor-normal interface is potentially a new prognostic factor for therapy response and survival outcome in patients with resected HCRM.

Maru DM, Kopetz S, Boonsirikamchai P, et al. Tumor thickness at the tumor-normal interface: a novel pathologic indicator of chemotherapy response in hepatic colorectal metastases. Am J Surg Pathol. 2010;34(9): 1287–1294.

Correspondence: Dr. Dipen M. Maru at dmaru@mdanderson.org
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Encapsulated papillary oncocytic neoplasms of the thyroid gland

Encapsulated papillary oncocytic neoplasms of the thyroid are rare tumors for which a relationship to other thyroid tumors has not been thoroughly elucidated. These tumors had been regarded as variants of papillary thyroid carcinoma (PTC), hyperplastic lesions, and follicular neoplasms. The authors retrieved 18 encapsulated papillary oncocytic neoplasms (EPONs) from their surgical pathology files and reviewed them for defining morphologic features. They excluded from their review cases having the typical nuclear features of PTC. They performed immunohistochemistry (IHC) for CK19, HBME1, and CD56. They completed microdissection, polymerase chain reaction, and sequencing of exon 15 of the BRAF gene and evaluated for transformation/papillary thyroid carcinoma RET/PTC rearrangement by fluorescence in situ hybridization. The authors found that the majority of the tumors exhibited a distinctive histologic appearance. They were composed of true papillae lined by a single layer of predominantly cuboidal cells with oncocytic cytoplasm; hobnailing typically was prominent. Three tumors showed taller cells with uniformly apical nuclei and no hobnailing. Ten of 18 cases showed vascular or capsular invasion, or both. Therefore, if the diagnostic criteria used to evaluate follicular neoplasms are applied, more than half of the tumors would be considered minimally invasive carcinomas. No cases were immunoreactive with antibodies to HBME1, and only one of 13 was immunoreactive for CK19. Six of seven interpretable cases were immunoreactive for CD56. No BRAF point mutations or RET/PTC rearrangements were identified in the examined cases. All patients were alive at the time of last followup, and no locally recurrent disease had been reported. However, one case was remarkable for a lymph node metastasis. The authors concluded that their results confirm that EPONs are histologically, immunohistochemically, and molecularly distinct from papillary thyroid carcinoma and seem to be most closely related to follicular neoplasms.

Woodford RL, Nikiforov YE, Hunt JL, et al. Encapsulated papillary oncocytic neoplasms of the thyroid: morphologic, immunohistochemical, and molecular analysis of 18 cases. Am J Surg Pathol. 2010;34(11):1582–1590.

Correspondence: Dr. Edward B. Stelow at es7yj@virginia.edu
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Fimbrial-ovarian carcinomas unified by altered p53, PTEN, and PAX2 expression

High-grade endometrioid and serous carcinomas of the ovary and fallopian tube are responsible for the majority of cancer deaths and comprise a spectrum that includes early or localized (tubal intraepithelial carcinoma) and advanced (invasive or metastatic) disease. The authors subdivided a series of these tumors into three groups and analyzed them for p53 mutations. The groups were classic serous; mixed serous and endometrioid; and endometrioid carcinomas. The authors also determined the frequencies of coexisting tubal intraepithelial carcinoma; frequency of a dominant ovarian mass suggesting an ovarian origin; and immunolocalization of WT-1, p53, PTEN, PAX2, and p16INK4. The authors found that 36 percent, 25 percent, and eight percent of the tumors in groups one through three were associated with tubal intraepithelial carcinoma (P=0.09), and in 34 percent, 45 percent, and 62 percent, respectively, the disease predominated in one ovary (P=0.028). Differences in frequencies of diffuse p53 immunostaining (85 to 93 percent), WT-1 (70 to 98 percent), and p16INK4 positivity (69 to 75 percent) were not significant for all groups. Greater than 95 percent reduction in PAX2 and PTEN occurred in 67 percent to 75 percent and five percent to 12 percent, respectively. However, PAX2 and PTEN staining intensity was often heterogeneous, highlighting different tumor populations. PAX2 and PTEN expression were markedly reduced or absent in 12 of 12 and four of 12 tubal intraepithelial carcinomas. The authors concluded that high-grade Müllerian carcinomas share identical frequencies of altered or reduced expression of p53, PTEN, and PAX2, all of which can be appreciated in tubal intraepithelial carcinomas. Because only a subset of these tumors appears to arise in the fallopian tube, attention to expression of these biomarkers in the ovary and other Müllerian sites might facilitate identification of other carcinogenic pathways. PAX2 and PTEN, in addition to p53 and p16INK4, are
a potentially important gene combination in high-grade pelvic carcinogenesis.

Roh MH, Yassin Y, Miron A, et al. High-grade fimbrial-ovarian carcinomas are unified by altered p53, PTEN and PAX2 expression. Mod Pathol. 2010:23;1316–1324.

Correspondence: Dr. C. P. Crum at ccrum@partners.org
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Prognostic significance of p16^INK4a and HPV in oropharyngeal cancer

The authors conducted a study to determine the prognostic importance of p16 and human papillomavirus in patients with oropharyngeal cancer treated in a phase III concurrent chemoradiotherapy trial. For the study, patients with stage III or IV head and neck squamous cell cancer were randomly assigned to concurrent radiotherapy and cisplatin with or without tirapazamine. Analyses were restricted to patients with oropharyngeal cancer. P16 was detected by immunohistochemistry and human papillomavirus (HPV) by in situ hybridization and polymerase chain reaction. Slides were available for p16 assay in 206 of 465 patients, of which 185 were eligible for the study, and p16 and HPV were evaluable in 172 patients. The authors found that 106 (57 percent) of 185 patients were p16 positive, and in patients evaluable for p16 and HPV, 88 (86 percent) of 102 p16-positive patients were also HPV positive. Patients who were p16 positive had lower T and higher N categories and better Eastern Cooperative Oncology Group (ECOG) performance status. When comparing p16-positive and p16-negative tumors, the authors found that the positive tumors were associated with better two-year overall survival (91 versus 74 percent; hazard ratio [HR], 0.36; 95 percent confidence interval [CI], 0.17–0.74; P=0.004) and failure-free survival (87 versus 72 percent; HR, 0.39; 95 percent CI, 0.20–0.74; P=0.003). P16 was a significant prognostic factor on multivariable analysis (HR, 0.45; 95 percent CI, 0.21–0.96; P=0.04). P16-positive patients had lower rates of locoregional failure and death due to other causes. There was a trend favoring the tirapazamine arm for improved locoregional control in p16-negative patients (HR, 0.33; 95 percent CI, 0.09–1.24; P=0.13). The authors concluded that HPV-associated oropharyngeal cancer is a distinct entity with a favorable prognosis compared with HPV-negative oropharyngeal cancer when treated with cisplatin-based chemoradiotherapy.

Rischin D, Young RJ, Fisher R, et al. Prognostic significance of p16INK4a and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol. 2010;28(27):4142–4148.

Correspondence: Dr. Danny Rischin at danny.rischin@petermac.org
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Breast carcinoma with amplified HER2: a gene expression signature for trastuzumab resistance

Recent trials have shown that a combination of trastuzumab and chemotherapy has remarkable efficacy in the adjuvant setting of breast cancer. Despite this, refractory breast cancer has emerged as a clinically problematic outcome for a subset of patients managed in this manner. In an effort to clarify and optimize the treatment regimens for breast cancer patients who are candidates to receive trastuzumab, the authors analyzed whether a distinctive genetic signature could be characterized that would reliably predict treatment outcome. The ability to predict who will respond and who will become refractory to this agent will improve clinical management of these patients and further stratify the personalized nature of this treatment regimen. The authors conducted a study in which 41 consecutive cases of breast carcinoma with well-documented amplification of the human epidermal growth factor receptor-2 gene and corresponding banked fresh-frozen tissue were identified and divided into two groups based on whether or not those patients received trastuzumab. The first group consisted of 12 patients who had received trastuzumab in the adjuvant setting, of which three eventually experienced tumor recurrence. The second group consisted of 10 patients who were not treated with trastuzumab, of which six were eventually found to have recurrence. Differentially expressed genetic profiles were determined using human genome-wide Illumina bead microarrays. The differentially expressed genes for nonrecurrence versus recurrence in the trastuzumab-treated group were distinct from those in the same comparison population within the untreated group. The authors concluded that the differential expression of key genes identified in this study might offer insight into a possible mechanism of trastuzumab resistance in breast carcinoma and that these genes may emerge as potential predictive biomarkers indicative of trastuzumab resistance.

Khoury T, Kanehira K, Wang D, et al. Breast carcinoma with amplified HER2: a gene expression signature specific for trastuzumab resistance and poor prognosis. Mod Pathol. 2010:23;1364–1378.

Correspondence: Dr. Thaer Khoury at thaer.khoury@roswellpark.org
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Initial margin status for invasive ductal carcinoma of the breast

Margin status of lumpectomy specimens is related to frequency of local recurrence. Optimal surgical technique requires microscopic margins free of carcinoma by at least 2 mm. Recurrence following lumpectomy is associated with residual carcinoma secondary to inadequate resection. The authors conducted a study to review a series of breast excisions to determine the frequency of residual carcinoma for positive, close, and negative margins. They reviewed lumpectomies and excisional biopsies for invasive ductal carcinoma that had subsequent re-excisions. Margin status of specimens was recorded as positive, less than 1 mm, 1 to 2 mm, or greater than 2 mm. The authors reviewed 123 lumpectomies and excisional biopsies of invasive ductal carcinoma with re-excision. Residual invasive carcinoma was found in 44 percent (17), 25 percent (six), 28 percent (eight), and 16 percent (five) of cases with positive, less than 1 mm, 1 to 2 mm, and greater than 2 mm margins, respectively. Residual invasive carcinomas were found in 57 percent (eight), 100 percent (five), 67 percent (two), and 100 percent (two) of mastectomies with positive, less than 1 mm, 1 to 2 mm, and greater than 2 mm margins, respectively, in the initial lumpectomy or excisional biopsy. The authors concluded that the frequency of residual invasive carcinoma was related to margin status of the original lumpectomy or biopsy. Even when margins were positive, most re-excisions were free of carcinoma. Residual invasive carcinoma was found in more than 25 percent of patients with margins of less than 2 mm, supporting re-excision for patients with margins of less than 2 mm. Sixteen percent of cases with margins greater than 2 mm harbored residual invasive carcinoma. Evaluation of margin status was complicated by tissue distortion and fragmentation.

Skripenova S, Layfield LJ. Initial margin status for invasive ductal carcinoma of the breast and subsequent identification of carcinoma in reexcision specimens. Arch Pathol Lab Med. 2010;134(1):109–114.

Correspondence: Dr. Lester J. Layfield at layfiel@aruplab.com
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Evaluation of lymph node counts in primary retroperitoneal lymph node dissection

Lymph node counts are a measure of quality assurance and are associated with prognosis for numerous malignancies. However, investigations of lymph node counts in testis cancer are lacking. Using the Memorial Sloan-Kettering Testis Cancer database, the authors identified 255 patients who underwent primary retroperitoneal lymph node dissection for nonseminomatous germ cell tumors (NSGCTs) between 1999 and 2008. They evaluated, using regression models, features that were associated with lymph node counts, positive lymph nodes, number of positive lymph nodes, and risk of positive contralateral lymph nodes. The median (interquartile range [IQR]) total lymph node count was 38 (IQR, 27 to 53 total lymph nodes), and it was 48 (IQR, 34 to 61 total lymph nodes) during the most recent five years. Features that were associated with higher lymph node count on multivariate analysis included high-volume surgeon (P=0.034), clinical stage (P=0.036), and more recent year of surgery (P<0.001), whereas pathologist was not significantly associated with lymph node count (P=0.3). Clinical stage (P<0.001) and total lymph node count (P=0.045) were closely associated with finding positive lymph nodes on multivariate analysis. The probability of finding positive lymph nodes was 23 percent, 23 percent, 31 percent, and 48 percent if the total lymph node count was less than 21, 21 to 40, 41 to 60, and more than 60, respectively. During a median followup of three years, all patients remained alive, and 16 patients developed recurrent disease, although no patients developed recurrent disease in the paracaval, interaortocaval, para-aortic, or iliac regions. The authors concluded that these results suggest that more than 40 lymph nodes removed at retroperitoneal lymph node dissection improve the diagnostic efficacy of the operation. These results will be useful for future trials comparing such dissections, especially when assessing the adequacy of lymph node dissection.

Thompson RH, Carver BS, Bosl GJ, et al. Evaluation of lymph node counts in primary retroperitoneal lymph node dissection. Cancer. 2010;116(22):5243–5250.

Correspondence information not available.
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